Techniques in combinatorial chemistry are gaining wide acceptance among modern methods for the generation of new pharmaceutical leads (Gallop, M. A. et al., 1994, J. Med. Chem. 37:1233-1251; Gordon, E. M. et al., 1994, J. Med. Chem. 37:1385-1401.). One combinatorial approach in use is based on a strategy involving the synthesis of libraries containing a different structure on each particle of the solid phase support, interaction of the library with a soluble receptor, identification of the `bead` which interacts with the macromolecular target, and determination of the structure carried by the identified `bead` (Lam, K. S. et al., 1991, Nature 354:82-84). An alternative to this approach is the sequential release of defined aliquots of the compounds from the solid support, with subsequent determination of activity in solution, identification of the particle from which the active compound was released, and elucidation of its structure by direct sequencing (Salmon, S. E. et al., 1993, Proc.Natl.Acad.Sci.USA 90:11708-11712), or by reading its code (Kerr, J. M. et al., 1993, J.Am.Chem.Soc. 115:2529-2531; Nikolaiev, V. et al., 1993, Pept. Res. 6:161-170; Ohlmeyer, M. H. J. et al., 1993, Proc.Natl.Acad.Sci.USA 90:10922-10926).
Soluble random combinatorial libraries can be synthesized using a simple principle for the generation of equimolar mixtures of peptides which was first described by Furka (Furka, A. et al., 1988, Xth International Symposium on Medicinal Chemistry, Budapest 1988; Furka, A. et al., 1988, 14th International Congress of Biochemistry, Prague 1988; Furka, A. et al., 1991, Int. J. Peptide Protein Res. 37:487-493). The construction of soluble libraries for iterative screening have also been described (Houghten, R. A. et al.1991, Nature 354:84-86). K. S. Lam disclosed the novel and unexpectedly powerful technique of using insoluble random combinatorial libraries. Lam synthesized random combinatorial libraries on solid phase supports, so that each support had a test compound of uniform molecular structure, and screened the libraries without prior removal of the test compounds from the support by solid phase binding protocols (Lam, K. S. et al., 1991, Nature 354:82-84).
When random combinatorial libraries are synthesized, however, representation of all possible structures can be achieved with near certainty only in cases in which the number of particles used for the synthesis is at least an order of magnitude higher than the number of synthesized structures (Burgess, K. et al., 1994, J. Med. Chem. 37:2985-2987).
For library construction, it would be desirable to perform the synthesis on a defined number of solid phase particles exactly matching the number of compounds of which the library is composed. This number is, generally, the product of the number of types of subunits at each of the predetermined number of "randomized" positions. For example, a library of three positions (trimers) in which each position can be occupied by one of five types of subunit has 5.times.5.times.5=125 species. With this ideal situation, we would be able to eliminate the statistical uncertainty of library generation by the split and mix procedure. An assay of the library might then be performed without "missing" an active compound or detecting the identical structure several times, which would be especially advantageous in the case of small libraries (the range of tens of thousands structures), where it is not unusual to find only single active compound (see e.g. (Stankova, M. et al., 1994, Drug. Develop. Res. 33:146-156)). Thus, there is a need in the art of synthesizing combinatorial libraries of a method to synthesize a library having each of the potential species of the library a predetermined number of times, preferably once.